Heather Has Three Parents

In the 1990s the children’s book, Heather Has Two Mommies, caused an uproar. To some people, the very title was ridiculous and, all by itself, seemed a powerful argument against childrearing by lesbian (or gay) couples. Today, it is more likely to provoke a “so what?”

Earlier this week an advisory committee of the U.S. Food and Drug Administration considered a proposal from Oregon researchers to begin human trials of a procedure for giving one woman’s eggs mitochondria from a different woman. One of arguments reminded me a lot of Heather. The NPR story on the FDA hearings started its discussion of the objections this way:

“One [objection] that’s got a lot of attention is that any babies made this way would technically have three genetic parents, they’d have DNA from the father’s sperm, from the mother’s egg, and from the woman who donated the healthy mitochondrial DNA.”

Alas, the reporter didn’t follow that statement with “so what?” But I will, after a little background.

The mitochondria (high school biology’s “energy powerhouses of the cell”) have their own very short stretch of DNA, separate from the 6.8 billion base pairs found on 46 chromosomes in the cell’s nucleus (the nuclear DNA). The 16,569 base pairs of the mitochondrial DNA (hereafter “mtDNA”) hold 37 (some say 38) genes, providing instructions for making 13 (or 14) proteins and another 24 RNA molecules. The full importance of these genes is unknown, but it is clear that some (happily rare) variations in the mtDNA cause quite severe illnesses. Unfortunately, each child gets all of its mitochondria (and hence its mtDNA) in the egg from its mother; if the mother’s mtDNA is dangerously flawed, so will be the mtDNA of all her children. With almost all other genetic diseases, no matter how inevitably the “bad” genetic variation leads to a disease (how “penetrant” the genetic variation is), a woman will have only a 50% or 25% chance of passing on the condition. With these, her genes can give rise to no healthy children.

The Oregon group’s proposal (and similar ideas from other groups, in the United States and elsewhere) would try to overcome this problem and allow women with a bad disease as a result of flawed mtDNA to have genetic children without passing on that disease. It would do so by, in effect, replacing the mitochondria in the prospective mother’s egg with mitochondria from a woman with normal mtDNA. (Several ways of accomplishing that have been proposed; the details don’t matter here.)

The result would be a child – let’s call her “Heather” – ­whose DNA was made up of about 3.4 billion base pairs (one set of chromosomes 1 through 22 plus an X or a Y chromosome) from his or her genetic father, 3.4 billion base pairs (one set of chromosomes 1 through 22 plus an X chromosome) from his or her mother, and 16,568 base pairs from the woman who served as the mitochondrial donor. Heather would have three parents. Or would she? And, if so, so what?

First, what does it mean to say someone is a “parent?” Let’s leave aside, for the moment, of the relationship between “genetic parent” and “parent.” Is the sperm donor whose parenting “effort” is over in a few moments comparable, at all, to the person who – sometimes with a more distant or even no genetic relationship – feeds, changes, clothes, bathes, and reads to a child, kissing its “ouchies” to make them go away? The donor makes a contribution of sorts (though usually a compensated one) but does he deserve the honorable title of “parent”?

The NPR reporter at least said “genetic” parent. (Not everyone has been so careful.) Does it make sense to call an mtDNA donor a “genetic parent”?[1] That is, does a contribution of roughly 0.0003% of someone’s human genetic sequences (and about 0.03% of their total human DNA) make the donor “a parent”?

If so, what about people who provide organ transplants? A heart, lung, kidney, or bone marrow donor provides a much higher percentage of a person’s human DNA. Why aren’t they new parents for the patient?

People whose DNA was used to provide the healthy version of a gene used in gene therapy, which is finally getting close to the clinic, may provide more base pairs than a mitochondria donor. Would they be parents?

Of course, most of the DNA in our bodies is not human DNA, in human cells, but microbial DNA from the thousands of microscopic species for whom we provide a meal ticket. Is an E. coli bacterium that gave rise to of billions of cells in our large intestine – containing far more DNA, and genes, both individually and collectively, than mitochondria ­– one of our parents?

What about retroviruses, recent or ancient, that “donated,” directly to us or to one of our ancestors, DNA that got stitched into the 6.8 billion base pairs of our nuclear DNA – are they parents? The “alu” repeat, a stretch of DNA with an average length of about 360 base pairs, is found about 500,000 times in each of our genomes. Is its prehistoric donor one of our parents, too?

“Stop quibbling!” you exclaim. In every single one of Heather’s (human) cells (or, at least, every one with mitochondria[2]), she has DNA that came to her from three people, whether or not you want to call them “parents.” No one else has that.

Not really. I have DNA from four people in each of my cells: my mother’s mother, my mother’s father, my father’s mother, and my father’s father. Actually, my DNA really came from all eight of my great-grandparents, and all 1024 of my great great great great great great great great grandparents, and all roughly one million of my great (18) grandparents. Yes, all that DNA passed through my (genetic) parents before coming to me, but why does that matter?

Heather gets her DNA from more than two people a bit differently from the way the rest of us do, but so what? How does getting what is, in effect, “gene therapy,” where the gene is delivered in a natural package called the mitochondrion, turn our hypothetical (and healthy) child into a powerful argument against the procedure?

It shouldn’t. Heather will not be getting superpowers, she will not be in any meaningfully way “designed” (except to avoid a nasty genetic disease), and she will not be given a newly made DNA sequence never before found in the human gene pool. She will get mitochondria with mtDNA that will allow her to have normal health, not a grave disease. That mtDNA will have been taken from a woman, who, though not a source of Heather’s nuclear DNA, is certainly a participant in the human gene pool.[3]

“Heather has three parents” is NOT an argument. It is an irrelevant but attention-getting slogan that is uncritically put forward as, and sometimes mistaken for, a real argument. Yes, the proposed process is a way of bringing forth living and healthy babies that is somewhat new and different, but so were obstetric forceps, (safe) C-sections, and in vitro fertilization. Novelty is not, in itself, a respectable argument against it.

Real and important arguments need to be had about these proposed experiments, but they are arguments about safety. Moving from non-human animals or in vitro studies to humans means putting at risk the health and even lives of the embryos, fetuses, babies, and eventual adults these new experiments create. First use in humans is never a step to be taken lightly; the risks can never be entirely eliminated or even foreseen in advance. Until you try something in humans, you just never know whether it will work and, if so, how well.

From the reporting of the hearing, the FDA Advisory Committee ­– if not necessarily the public commenters or the press – did focus on safety. Are we confident that this procedure is safe enough to move from petrie dishes and monkeys to human babies? What other steps could be done to give us more confidence before putting human lives at stake? Those are good medical and scientific issues – as well as profoundly ethical issues. I do not know enough of the science presented to have a strong view on what the answer should be now and I am glad FDA is being advised by a committee that does have relevant expertise and knowledge.

But I do know enough to sniff out a meaningless argument when I hear it. “Heather has three parents” is bogus. People should stop making it. And the press should stop taking it seriously.

Hank Greely

[1] I presume no one thinks the mtDNA donor would be entitled to the legal status of “parent.” That would, I trust, be laughed out of any court.

[2] Red blood cells, for example, have no DNA, nuclear or mitochondrial.

[3] In fact, to minimize the risk, if any, of a mismatch between the nuclear DNA and the mtDNA, I suspect researchers would be likely to use mtDNA from women whose mtDNA was quite similar to the prospective mother’s – the two women would probably share maternal ancestors.

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Ricki Lewis

March 3, 2014 at 12:03 am

Hank, I listened to all 8 hours of the FDA hearing and wrote up the science part for Medscape. I was working on this week’s blogpost (I write the “DNA Science” blog at Public Library of Science), and found your post on facebook.

It is far better than what I was going to post! What an enormous relief to find someone who agrees with me that the “3 parent designer genetically engineered scary monster” media take is ridiculous.

I’ll probably post anyway and include some of the quotes from the public comment part. Parts were reasonable, but many veered towards hysteria. Great, great job!

Hank Greely

March 9, 2014 at 1:26 am

Ricki – thank you for your kind comment. I have planning to follow up this post with two more (making a “Heather trilogy”); we’ll see when, or if, time allows. But if I don’t, I’m glad that you already said a lot of what I wanted to say (and more) in your post at http://blogs.plos.org/dnascience/.